Low-Dose tPA in Ischemic Stroke – The ENCHANTED Trial

Background

Thanks to Salim Rezaie for providing pre-publication peer review for this post. This post is cross-posted on REBEL EM here.

Despite continued debate on the efficacy of alteplase (tPA), it currently remains one of the major interventions directed at patients presenting with acute ischemic stroke. The current standard dose of the drug is 0.9 mg/kg given over 1 hour. It is unclear whether lower doses would be equally effective in increasing good neurologic outcomes after stroke while simultaneously decreasing the rate of intracerebral hemorrhage (ICH); the most serious side effect. Evidence showing that lower doses of tPA are non-inferior to standard-dose tPA could lead to a shift in treatment.

Clinical Question

Is low-dose tPA non-inferior to standard-dose tPA in terms of death or disability at 90 days in the treatment of acute ischemic stroke presenting within 4.5 hours of symptom onset?

Population

Patients > 18 years of age with a clinical diagnosis of acute ischemic stroke who met guideline recommended criteria for treatment with intravenous tPA within 4.5 hours of symptom onset. Patients had to be independent at baseline (mRS < 1).

Intervention

Low-dose (0.6 mg/kg) tPA (administered as 15% of dose as IV bolus followed by 85% of dose as infusion over 1 hour)

Control

Standard-dose (0.9 mg/kg) tPA (administered as 10% of dose as IV bolus followed by 90% of dose as infusion over 1 hour)

Outcomes

Primary: Death or disability (mRS = 2-6) at 90 daysSecondary: ICH, Mortality at 7 and 90 days

Design

Multicenter, prospective, randomized, open-label trial

Excluded

Unlikely to benefit from the therapy due to pre-existing disability
Another medical illness interfered with the outcome assessment
Unlikely to adhere to follow up
Unable to consent
Previously enrolled in the ENCHANTED study

Primary Results

Non-inferiority prespecified as an upper limit for non-inferiority of 1.14. This noninferiority margin was derived from a Cochrane meta-analyses of alteplase

Critical Results

Primary Outcome: Death or Disability (mRS = 2-6) at 90 days

Low-dose tPA: 53.2% (855/1607)

Standard-dose tPA: 51.1% (817/1599)

OR: 1.09 (95% CI: 0.95-1.25)

Secondary Outcomes

Mortality (7 days)

Low-dose tPA: 3.6%

Standard-dose tPA: 5.3%

OR: 0.67 (95% CI: 0.48 – 0.94)

Mortality (90 days)

Low-dose tPA: 8.5% (17/1654)

Standard-dose tPA: 10.3% (35/1643)

OR: 0.80 95% CI: 0.63-1.01

Intracerebral Hemorrhage

Low-dose tPA: 1% (17/1654)

Standard-dose tPA: 2.1% (35/1643)

OR: 0.48 (95% CI: 0.27-0.86)

Strengths

Large study asking a clinically relevant question with important patient centered outcomes being considered

Assessors of outcomes at follow up were blinded to treatment allocation

Loss to follow up was minimal in both arms (low dose: 47, standard dose: 44)

Limitations

Open label study design opens up trial to numerous biases

Co-primary endpoint (death or disability)

It is unclear whether patients were recruited consecutively or not

> 60% of patients were of Asian descent which may limit external validity

Follow-up at 28 and 90-days done by in-person and telephone interview. Heterogeneity of assessment approach may lead to imprecise results

The authors of the study had significant conflicts of interest

Author's Conclusions

“This trial involving predominantly Asian patients with acute ischemic stroke did
not show the noninferiority of low-dose alteplase to standard-dose alteplase with
respect to death and disability at 90 days. There were significantly fewer symptomatic intracerebral hemorrhages with low-dose alteplase.”

Our Conclusions

Low-dose tPA did not meet the upper limit of the prespecified non-inferiority threshold for the odds ratio in comparison to standard-dose tPA for the primary outcome of death or disability at 90 days. However, low-dose tPA performed extremely well in this study. Low-dose tPA patients were more likely to be alive at both 7 and 90 days with a lower ICH rate.

Potential Impact To Current Practice

As this study did not show non-inferiority of the low-dose tPA approach, we do not think it will alter overall treatment strategies. However, in patients with CVA who are eligible for systemic thrombolytics and in whom the doctor and patient both think would benefit from the drug but have increased risk of bleeding, low-dose tPA may be provide an alternative approach.

Bottom Line

Low-dose tPA achieved similar outcomes to standard-dose tPA with lower mortality and ICH rates. Although this study does not prove non-inferiority of low-dose tPA, it also does not show superiority of standard-dose tPA.

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by Anand Swaminathan, MD, MPH

Anand "Swami" Swaminathan is an assistant professor of Emergency Medicine in the Ronald O. Perelman Emergency Department and assistant residency director of the NYU/Bellevue Emergency Medicine residency program. His interests are in resuscitation medicine, resident education and cutting the knowledge translation window. Swami is an active contributor and supporter of innovations in medicine, particularly Free Open Access Medical Education (FOAM). He is a contributor to a number of sites including ALiEM, LITFL, ERCast, and The SGEM. Swami is an associate editor for REBEL EM and REBEL Cast. He is also faculty for the Essentials of Emergency Medicine and Deputy Editor of EM: RAP.